The human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS), a major cause of mortality and morbidity in many parts of the world. Development of an effective vaccine against this virus will facilitate the control of the disease. Hypothesis: The hypothesis is that a vaccine which induces a HIV-specific humoral and cellular immune response will be capable of protecting against HIV infection or the progression to AIDS. This hypothesis will eventually be tested in the SIV-rhesus macaque animal model system. SPECIFIC AIM 1: The objective is to induce an anti-SIV humoral immune response that will account for the high variability of the viral envelope glycoprotein. A mixture of peptides representing the in vivo variability of the hypervariable epitopes of the SIV envelope will be synthesized [such peptide mixtures are termed Hypervariable Epitope Constructs (HECs)] and chemically attached to the surface of recombinant-envelope glycoprotein (gpl30) to add variability to the molecule. SPECIFIC AIM 2: HECs will be individually evaluated for their ability to evoke humoral and cellular immune responses. We expect extensive antibody cross-reactivity and will assay for in vitro neutralization against many divergent strains of SIV. We will also evaluate and compare T cell proliferative and CTL responses. SPECIFIC AIM 3: The objective is to induce an anti-SIV cellular immune response. A series of Bacille Calmette-Guerin (BCG) recombinants expressing individual SiVmac239 proteins will be prepared, ultimately representing the entire protein encoding region of SiVmac239. SPECIFIC AIM 4: The individual BCG recombinants will be evaluated for their ability to evoke cellular and humoral immune responses. CTL responses will be assayed using three strains of inbred mice, each strain possessing a different MHC restriction. SPECIFIC AIM 5: The objective is to determine the capacity of the combination of the HECs and BCG recombinants to induce a humoral and cellular anti-SIV immune response. The HECs and the recombinant BCGs will be introduced into mice at the same time. The immunogenicity of this combination vaccine in several strains of inbred mice representing divergent MHC restrictions will be determined. SPECIFIC AIM 6: Outbred mice will be immunized with the combination vaccine to mimic better the eventual immunization of outbred rhesus macaques with this SIV combination vaccine. Significance: This project will test the capacity of a combination vaccine to induce a virus-specific cellular and humoral immune response and allow the development of an effective vaccine against HIV.